A high HBV viral load has been implicated in both disease progression and resistance to antiviral therapy in Asian adults; however this role has not been clarified in other populations such as children and non-Asian adults (both of which typify our Baltimore population of HBV-infected individuals.) Furthermore, viral determinants of HBV viral replication rates have not been fully elucidated in any population. Our group has recently reported two findings which could shed new light on these determinants: 1) Methylation of HBV DNA occurs in non-integrated as well as integrated HBV and may down regulate viral replication and 2) The novel double mutant HBV 1762T/1764A, with overlapping sequences for the HBV core promoter and the HBV S gene, increases viral replication in Asian adults. This mutant has greater sensitivity and specificity for both diagnosing and predicting hepatocellular carcinoma (HCC) in Asian adults compared to other HCC biomarkers. We propose to use these novel findings in both a database and a clinical trial. The database will contain all HBV-infected individuals cared for in the Johns Hopkins Medical Institutions which we estimate will contain ~ 100 children and adolescents and ~650 adults of whom - 50% are African American, 300 are HBV/HIV co-infected; 150 are HBV/HIV/HCV tri-infected, and 50 have HCC. For the database protocol we will analyze sera for both HBV DNA methylation and the double mutant to test two hypotheses: 1) In patients with methylated serum HBV DNA, HBV DNA viral load will be lower compared to patients with non-methylated serum HBV DNA and 2) In patients with HBV HCC, HBV viral loads will be higher, HBV DNA methylation rates lower, and the double mutant frequency increased compared to age and sex-matched HBV-infected controls. The clinical trial will be a sequential randomized controlled trial in immunotolerant subjects 5 - 21 years (HBsAg+,HBeAG+, HBV DNA >10(4)cpm), to determine if lowering the HBV viral load by a nucleoside analogue(NA) followed by an immunomodulator will improve response compared to (NA) alone. Group 1 will receive entecavir(ETV) for 8 weeks followed by pegylated interferon + ETV for 40 weeks; Group 2 will receive ETV alone. Response will be defined by HBeAg loss/ HBV DNA < 200 cpm at 48 weeks. [unreadable] [unreadable]